Dual stimuli-responsive hydrogels and their synthetic methods

ABSTRACT

The present invention relates to a process for preparing copolymer hydrogels with controlled molecular weights and having both thermo- and pH-responsive properties, wherein the process comprises the steps of (a) providing sulfonamide type styrenic or (meth)acrylamide-based monomers exhibiting different pK a  values; (b) providing poly(N-isopropylacrylamide) or crosslinked poly(N-isopropylacrylamide-co-methylene bisacrylamide) hydrogels having thermo-responsive properties; and (c) providing several hydrogels exhibiting pH-sensitive properties and random or block copolymerizations of the sulfonamide type styrenic or (meth)acrylamide-based monomers prepared in step (a) with N-isopropylacrylamide and/or methylene bisacrylamide monomers used in step (b) in a polar or non-polar solvent; wherein said steps (b) and (c) are carried out by controlled/living radical polymerization using alkyl halides as the initiators and the transition metals with phosphine or amine ligands as the catalysts. The present invention also relates to the copolymer hydrogels made by the aforesaid process.

FIELD OF THE INVENTION

[0001] The present invention relates to polymeric materials which aredual stimuli-responsive (DSR) to changes in both the temperature and pHof a human body, and a process for preparing such materials.

BACKGROUND OF THE INVENTION

[0002] An important ingredient for a drug delivery system (DDS) includesspecial materials for encapsulating or charging the active drug.Stimuli-responsive materials that have been used as such specialmaterials up to now are described in Y. H. Bae, Controlled DrugDelivery: Challenges and Strategies, K. Park, Ed., Am. Chem. Soc., Chap.8, pages 147-162, Washington, D.C. (1997).

[0003] Among the stimuli-responsive materials,poly(N-isopropylacrylamide) has been well known as a special polymermatrix for drug delivery because this polymer can exhibit athenno-responsive property depending on the change of human bodytemperature. It also exhibits a physical property specific for the lowercritical solution temperature (LCST).

[0004] Polymeric electrolytes obtained by polymerizing vinylic monomershaving carboxyl acid, sulfonic acid, an amine or an ammonium group havebeen used as pH-responsive hydrogels such as described inPolyelectrolyte Gels; Properties, Preparation, and Applications,” R. S.Harland and R. K. Prud'homme, Eds., ACS Symp. Series # 480, Am. Chem.Soc., Chap. 17, page 285, Washington, D.C. (1992).

[0005] Known “intelligent” polymeric materials having DSR propertyinclude a copolymer obtained by grafting a pH-responsive enzyme onto athermo-responsive material. Problems associated with preparing existingDSR material include difficulty in control of the molecular weight ofthe hydrogel formed, wherein the molecular weight may determine drugdelivery efficacy.

SUMMARY OF THE PRESENT INVENTION

[0006] Accordingly, it is an object of the present invention to providerandom or block hydrogel copolymers having both thermo- andpH-responsive properties.

[0007] Another object of the present invention is to provide a methodfor controlling the molecular weight of the random or block hydrogelcopolymers, which affects both the thermo- and pH-responsive properties.

[0008] Other objects of the present invention will become apparent tothose skilled in the art after having the benefit of this disclosure.

[0009] The present invention provides novel materials exhibiting DSR(dual stimuli-responsive) property such as both thermo and pH-responsiveproperties, and also covers a process of preparing these substances byatom transfer radical polymerization, wherein said process comprises thesteps of: synthesizing sulfonamide-type vinylic monomers havingpH-responsive properties; and, copolymerizing N-isopropylacrylamide ormethylene bisacrylamide monomer having thermo-responsive property, withsulfonamide-type monomers to produce random or block copolymersexhibiting both pH-responsive and thermo-responsive properties.

[0010] As used herein, the term atom transfer radical polymerization(ATRP) also refers to “control/living” radical polymerization which iswell described in the literature (T. E. Patten and K. Matyjaszewski,Adv. Mater:, 10, 10:901, 1998).

DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0011] The present invention provides a process for preparing hydrogelshaving both thermo- and pH-responsive properties with controlledmolecular weights, which comprises the steps of:

[0012] (a) synthesizing sulfoneamide type of vinyl monomers havingpH-responsive properties;

[0013] (b) preparing poly(N-isopropylacrylamide) or its copolymer withmethylene bisacrylamide having thermo-responsive property; and

[0014] (c) random or block copolymerizing said pH-responsive monomerswith thermo-responsive monomers; wherein said steps (b) and (c) arecarried out by controlled/living radical polymerization usingphosphine-based or amine-based transition-metal catalysts and alkylhalogen initiators.

[0015] The pH-responsive sulfoneamide type of styrene derivativesaccording to the present invention are monomers represented by thefollowing formula (1) or (2).

[0016] wherein,

[0017] R₁ is selected from the group consisting of phenyl, isoxazole,acetyl, methizole, dimethoxine, diazine, methoxypyridazine, methazine,isomidine and pyridine.

[0018] The compound of the following formula (3) is prepared byfollowing the procedures described in S. Y. Park and Y. H. Bae,Macromol. Rapid Commun., 20:269 (1999), and can be used as the(meth)acrylamide type monomer carrying a sulfonamide group of thepresent invention.

[0019] wherein

[0020] R₁ is defined as above and R₂ is hydrogen or a methyl group.

[0021] The catalysts used in the present invention are the complexes ofcopper halide and the following ligands, bipyridine, iron halide anddiimine, ruthenium halide and phosphines, nickel halide and phosphines,and the like. The preferred catalysts are the complexes of nickel halideand phosphines, iron halide and amine, and copper halide and amine.

[0022] The phosphines used in the present invention arebis(diphenylphosphino)ethane, bis(dimethylphosphino)ethane,bis(triphenyl) phosphine [(Ph₃P)₂], or bis(trimethyl) phosphine([(CH₃)₃P]₂), and the like.

[0023] The amines used in the present invention include 2,2′-bipyridine,pentamethyl-diethylenetriamine, tris[2-(dimethylamino)ethyl]amine; (Me)₆Tren, and the like.

[0024] Specifically, the phosphine-based nickel and iron catalystsinclude the compounds of the following formula (4) or (5)

[0025] R₁ to R₅ are independently selected from the group consisting ofmethyl, phenyl, iso-propyl, tert-butyl and ethyl;

[0026] Mt is nickel or iron; X is chlorine or bromine; and n is aninteger of 1 to 3.

[0027] The amine-based copper catalysts used in the present inventionhave amine-based ligands represented by the following formulas (6) to(8):

[0028] wherein R represents H, 5-nonyl or n-heptyl.

[0029] wherein R represents n-propyl or n-butyl.

[0030] wherein n represents 1, 2 or 3.

[0031] Generally, alkyl halides are used as the initiators in thepresent invention.

[0032] The solvents used in the present invention include polarsolvents, such as dimethyl formamide, dimethyl sulfoxide,tetrahydrofuran, distilled water, solvents containing halogens, loweralcohols, or the mixtures thereof; and non-polar solvents, such ashexane, toluene, benzene or cyclohexane.

[0033] According to the present invention, the block copolymers can beprepared in the suitable temperature range of −78° C. to 150° C., moresuitably between −50° C. to 30° C.

[0034] The DSR hydrogels prepared according to the present invention arerepresented by the following formulas (9) to (14):

[0035] wherein

[0036] R₁ is selected from the group consisting of phenyl, isoxazole,acetyl, methizole, dimethoxine, diazine, methoxypyridazine, methazine,isomidine and pyridine;

[0037] R₂ represents hydrogen or methyl;

[0038] m is 5 to 500, preferably 50 to 300;

[0039] n is 3 to 500, preferably 5 to 100; and

[0040] the ratio of y/x ranges from 2/98 to 8/92.

[0041] The present invention is further illustrated by the followingexamples, but such examples are not intended to limit the invention inany way.

EXAMPLES Example 1

[0042] The styrene-based monomer of4-vinylbenzoyl-4-amino-N-(4,6-dimethyl-2-pyrimidyl) benzenesulfonamideexhibiting a pH-responsive property was synthesized by reactingsulfamethazine having the pK_(a) value of 7.4 with 4-vinylbenzoic acid.

[0043] 5 g of 4-vinylbenzoic acid and 0.34 mole of triethylamine weredelivered into a 500 mL, 3 neck round bottom flask equipped with areflux system under inert nitrogen gas, followed by adding 150 mL oftetrahydrofuran. Subsequently, 0.34 mole of ethylchlorofonnate wasinjected thereto at −20° C. and the reactor was stirred for 1 h.

[0044] To the resulting solution in the reactor, 0.34 mole ofsulfamethazine dissolved in 200 mL of tetrahydrofuran, was delivered byusing a syringe, followed by reacting for another 1 h. After thereaction was completed, the resulting product was washed with aqueousHCl (1 N) and aqueous Na₂CO₃ solution, at least three times. Theresulting white solid was purified by re-crystallization in a mixture ofacetone-hexane (1/1, v/v). The yield of the purified monomer was 55% onthe basis of the incipient amount of reagents used.

Example 2

[0045] The styrene-based monomer of4-vinylbenzoyl-3-(p-aminobenzensulfamido)-6-methoxypyridazine wassynthesized by reacting 0.34 mole of sulfamethoxypyridazine having thepK_(a) value of 6.7 under the same conditions described in Example 1,followed by purification of the resulting product. The yield of theresulting monomer was 42%.

Example 3

[0046] The styrene-based monomer of4-vinylbenzoyl-2,4-dimethoxy-6-sulfanylamido-1,3-diazine was synthesizedby reacting 0.34 mole of sulfamethoxine with 4-vinylbenzoic acid underthe same conditions as Example 1. The yield of the resulting monomer was62%.

Example 4

[0047] 5 g (0.0125 mol) of diphenylphosphinoethane and 1.7 g (6.25×10⁻³mole) of nickel(II) bromide hydrate (NiBr₂·3H₂O) were dissolved in 50 mLof ethanol, respectively. The two solutions were then mixed in a 250 mLround bottom flask, followed by reacting at room temperature for 3 hwith stirring. Subsequently, ethanol was removed, followed by adding 160mL of a mixture of acetone/benzene (3/5, v/v). The resulting solutionwas stirred to obtain a dark blue crystal, followed by adding 2.14 g ofnickel (II) bromide hydrate dissolved in 100 mL of ethanol. Thereactants were refluxed at 80° C. for 1 h resulting in production of adark red precipitate. This precipitate was dissolved into 500 mL ofethanol, and the un-dissolved portion was removed by filtration. Theremaining solution was dried in a vacuum oven and 5 g of a complex ofdiphenylphosphinoethane and nickel (II) bromide was obtained. Thiscomplex was dissolved in 100 mL of toluene, to be used as the catalystof the present invention.

Example 5

[0048] The catalyst (5×10⁻⁵ mol) prepared in Example 4 was reacted withmethyl 2-bromo-propionate (1×10⁻⁴ mol) at 25° C. under inert nitrogengas with stirring for 5 min to obtain the initiator for ATRP.

[0049] Subsequently, 2.26 g (0.02 mole) of N-isopropylacrylamide (NiPAM)was delivered into a 250 mL 3-neck flask using a syringe under the inertnitrogen gas, followed by adding 5 mL of dimethylformamide anhydrate.

[0050] The air in the reactor was then removed by purging with nitrogengas at 90° C. for 30 min, followed by delivering the initiator solutioninto the reactor using a syringe and polymerizing the solution withstirring for 3 h. This solution was precipitated in hot water. Afterfiltration, it was dried. Finally, 2.1 g of poly(N-isopropylacrylamide)with average molecular weight 25,000 g/mol and 1.34 polydispersity, wasobtained. The molecular weight was determined by both ¹H NMR and sizeexclusion chromatographic analysis at room temperature.

Example 6

[0051] 4 g of the sulfonamide type of styrene derivative prepared inExample 1 was polymerized by following the same procedures as in Example5. 2.8 g of hydrogel with molecular weight 12,000 g/mol was obtained byfollowing the steps described in Example 5.

Example 7

[0052] After 20 mL of poly(N-isopropylacrylamide) (PNiPAM) solutionprepared in Example 5 was taken using a syringe, 2 g of thesulfonamide-based styrene derivative in Example 1 was dissolved in 100mL of dimethylsulfoxide and added into the reactor. The reactiontemperature increased to 120° C. and the polymerization was performedwith stirring for 6 h. After completion of the reaction, a part ofsolvent was removed by distillation, then 50 mL of the solution wasprecipitated in 500 mL of diethyl ether and filtered. 1.5 g of blockhydrogel of poly(N-isopropylacrylamide -b-styrenic sulfonamide) withmolecular weight 32,000 g/mol was obtained, in which there were 220repeating units of NiPAM and there were 17 repeating units of styrenicsulfonamide on the basis of ¹H NMR analysis.

Example 8

[0053] Under the same reaction conditions as described in Example 7, 2 gof the sulfonamide-based styrene derivative prepared in Example 2 waspolymerized. 1.6 g of block hydrogel ofpoly(N-isopropylacrylamide-b-styrenic sulfonamide) with averagemolecular weight 29,000 g/mol was obtained, in which there were 220repeating units of NiPAM and there were 10 repeating units of styrenicsulfonamide on the basis of ¹H NMR analysis.

Example 9

[0054] Under the same reaction conditions as shown in Example 7, 2 g ofthe sulfonamide-based styrene derivative prepared in Example 3 waspolymerized. 1.4 g of the block hydrogel of poly(NiPAM-b-styrenicsulfonamide) with average molecular weight 36,000 g/mol was prepared, inwhich there were 220 repeating units of NiPAM and there were 25repeating units of styrenic sulfonamide on the basis of ¹H NMR analysis.

Example 10

[0055] According to the method described in the literature (S. Y. Parkand Y. H. Bae, Macromol. Rapid Commun., 1999, 20, 269.), the reaction of3 mL of methacryloyl chloride and 10 g of sulfamethoxypyridazineexhibiting a pK_(a) value of 6.7 produced 8 g of sulfamethoxypyridazinylmethacrylamide as a methacrylamide type monomer carrying a sulfonamidegroup. This was purified prior to use. Under the same reactionconditions as in Example 5, 3 g of N-isopropylacrylamide was polymerizedin dimethylformamide (50 mL) at 25° C. for 24 h. The molecular weight ofthe resulting poly(N-isopropylacrylamide) was 28,000 g/mol. 3 g of thesulfonamide-based methacrylamide dissolved in 50 mL of dimethylformamide(DMF) was delivered into the reactor using a syringe, followed byco-polymerization at 90° C. for 6 h. The resulting polymer was purifiedby following the same procedures as described in Example 7. 5.1 g ofblock hydrogel of poly(N-isopropylacrylamide-b-sulfamethoxypyridazinylmethacrylamide) with average molecular weight 40,000 g/mol was obtained,in which there were 248 repeating units of NiPAM and there were 34repeating units of sulfamethoxypyridazinyl methacrylamide on the basisof ¹H NMR analysis.

Example 11

[0056] 2 g of 4-hydroxystyrene was dissolved in 100 mL oftetrahydrofuran (THF), and 3.2 g of trimellitic anhydride chloride and2.6 mL of triethylamine (96%) were delivered into the reactor, followedby reaction at 30° C. with stirring for 6 h. The resulting product wasdissolved into an excess of methanol, followed by re-crystallization.4.1 g of the resulting styrene derivative carrying the anhydride group,4-[(1,3-dioxo-5-phthalanecarbonyl)oxy]styrene was obtained. This styrenederivative was charged into a 250 mL 3-neck flask, followed by adding100 mL of DMF and 4.5 g of sulfamethazine with pK_(a) of 7.4. Thereaction was then carried out at 50° C. with stirring for 6 h. 6.5 g ofthe corresponding styrene derivative having both carboxyl andsulfamethazine groups,4-[(1-sulfamethazinylamido-2-carboxyl-5-phthalane-carbonyl) oxy]styrene,was obtained by re-crystallization using ethanol.

Example 12

[0057] 3.0 g of the same styrene derivative having the anhydride groupas prepared in Example 11 and 4.2 g of sulfadimethoxine (FW: 310.3) withpK_(a) 6.1 were reacted in the same manner as described in Example 11.6.5 g of the corresponding styrene derivative having carboxyl andsulfadimethoxyine groups,4-[(1-sulfamethoxinylamido-2-carboxyl-5-phthalanecarbonyl) oxy]styrene,was obtained.

Example 13

[0058] Under the same conditions as in Example 12, the reaction with 3.5g of sulfadiazine (FW: 250.3) having pK_(a) of 6.52 produced 5.5 g ofthe corresponding styrene derivative,4-[(1-sulfadiazinylamido-2-carboxyl-5-phthalanecarbonyl)oxy]styrene.

Example 14

[0059] Under the same conditions as in Example 12, the reaction of thestyrene derivative with 4.0 g of sulfapyridine (FW: 249.3) with pK_(a)of 8.43 produced 5.7 g of the corresponding styrene derivative,4-[(1-sulfapyridinylamido-2-carboxyl-5-phthalanecarbonyl)oxy]styrene.

Example 15

[0060] Under the same conditions as in Example 12, 4.0 g ofsulfabenzamide (FW: 276.3) exhibiting pK_(a) of 4.57 was reacted withthe styrene derivative resulting in the production of 6.0 g of thecorresponding styrene derivative,4-[(1-sulfabenzamido-2-carboxyl-5-phthalanecarbonyl) oxy]styrene.

Example 16

[0061] 3 g of N-isopropylacrylamide was charged in a 250 mL 3-neck flaskunder inert nitrogen gas, followed by adding 100 mL of distilled waterusing a syringe. CuBr/Me₆TREN (tris[2-(dimethylamino)ethyl]amine)(5.0×10⁻⁵ mole) was used as the catalyst and methyl-2-bromopropionate(1.0×10⁻⁴ mole) was used as an initiator, which were injected into thereactor. Polymerization was performed at room temperature for 24 h,followed by termination and purification. 2.9 g ofpoly(N-isopropylacrylamide) hydrogel with average molecular weight22,000 g/mol was obtained.

Example 17

[0062] 3 g of pure sulfamethoxypyridazinyl methacrylamide prepared inExample 10 was polymerized by following the same procedures as describedin Example 16, followed by termination and purification. 2.5 g of thecorresponding hydrogel with average molecular weight 25,000 g/mol wassynthesized.

Example 18

[0063] Under the same conditions as in Example 16, 2.5 g ofpoly(N-isopropylacrylamide) (MW:20,000) was first prepared by ATRP,followed by adding 1.5 g of sulfadimethoxinyl methacrylamide into thereactor and copolymerizing at room temperature with stirring for 24 h.3.8 g of poly(N-isopropylacrylamide)-b-sulfadimethoxinyl methacrylamide)copolymer was obtained, in which there were 177 repeating units of NiPAMand there were 32 repeating units of—sulfadimethoxinyl methacrylamide onthe basis of ¹H NMR analysis. In addition, poly(sulfadimethoxinylmethacrylamide) was first synthesized by using 1.5 g of thecorresponding monomer via ATRP using 4-bromomethyl sodium benzoateinstead of methyl-2-bromopropionate as the initiator, followed by addingNiPAM monomer and polymerizing it. Consequently, the correspondinghydrogel having the same composition was also synthesized.

Example 19

[0064] Under the same conditions as in Example 16, 3.5 g ofN-isopropylacrylamide and methylene bisacrylamide (98/2, mol/mol) werecopolymerized for 16 h. 2.4 g of the cross-linked hydrogel with 2 mol %of the degree of cross-linking was prepared. 1.5 g of sulfadimethoxinemethacrylamide monomers was again delivered into the reactor andpolymerized at room temperature with stirring for 24 h. 4.8 g ofpoly[(N-isopropylacrylamide-co-methylenebisacrylamide)-b-sulfadimethoxyl methacrylamide] core-shell type blockcopolymer was synthesized.

Example 20

[0065] 1.5 g of4-[(1-sulfamethazinylamido-2-carboxyl-5-phthalanecarbonyl)oxy]styreneprepared in Example 11 was polymerized under the same conditions asdescribed in Example 16. 0.8 g of the corresponding hydrogel havingaverage molecular weight 7,000 g/mol was obtained.

Example 21

[0066] 1.5 g of4-[(1-sulfamethazinylamido-2-carboxyl-5-phthalanecarbonyl)oxy]styreneprepared in Example 11 was polymerized under the same conditions as inExample 18. 3.9 g of the corresponding block copolymer was synthesized.

Example 22

[0067] 1.5 g of the styrene derivative,4-[(1-sulfamethazinylamido-2-carboxyl-5-phthalane-carbonyl)oxy]styrene,prepared in Example 11 was polymerized under the same conditions as inExample 19. Correspondingly, 5.8 g of crosslinked block hydrogel,poly[(N-isopropylacryl-amide-co-methylenebisacrylamide)-b-4-[(1-sulfamethazinylamido-2-carboxyl-5-phthalane-carbonyl)oxy]styrene]was obtained.

Example 23

[0068] 2.0 g of pure sulfamethoxypyridazinyl methacrylamide prepared inExample 10 and 2.0 g of N-isopropylacrylamide were charged into a 250 mL3-neck flask under inert nitrogen gas, followed addition of 100 mL ofdistilled water using a syringe. CuBr/Me₆TREN (5.0×10⁻⁵ mole) as thecatalyst prepared above and methyl-2-bromopropionate (1.0×10⁻⁴ mole) asthe initiator, were then injected and polymerized at room temperaturewith stirring for 24 h. 3.9 g ofpoly(N-isopropylacrylamide-co-sulfamethoxypyridazinyl methacrylamide)random hydrogel copolymer with average molecular weight 39,000 g/mol wasobtained. The conversion was over 98% on the basis of ¹H NMR analysis.

Example 24

[0069] 2.0 g of sulfamethoxypyridazinyl methacrylamide prepared inExample 10 and 2.0 g of N-isopropylacrylamide/0.02 g of methylenebisacrylamide were charged into a 250 mL 3-neck flask under nitrogengas, followed by delivery of 100 mL distilled water using a syringe.CuBr/Me₆TREN complex (5.0×10⁻⁵ mole) as the catalyst andmethyl-2-bromopropionate (1.0×10⁻⁴ mole) as the initiator were injectedand reacted at room temperature with stirring for 24 h. 3.9 g of thecorresponding cross-linked random hydrogel copolymer was synthesized.The conversion was over 97% on the basis of ¹H NMR analysis. Thedetermnination of molecular weight for the cross-linked material wasimpossible, and ¹H NMR analysis was obtained by dissolving the materialinto a solvent after drying and obtaining powder by grinding.

Example 25

[0070] 1.5 g of4-[(1-sulfamethazinylamido-2-carboxyl-5-phthalanecarbonyl)oxy]styreneprepared in Example 11 was polymerized under the same conditions as inExample 23. 3.1 g ofpoly(N-isopropylacrylamide-co-4-[(1-sulfamethazinylamido-2-carboxyl-5-phthalanecarbonyl)oxy]styrene) random hydrogel copolymer with average molecular weight29,000 g/mol was synthesized, in which the conversion was 88 mol % basedon the incipient amount of monomers used.

Example 26

[0071] 2.0 g of4-[(1-sulfamethazinylamido-2-carboxyl-5-phthalanecarbonyl)oxy]styreneprepared in Example 11 was synthesized under the same conditions asExample 24. 3.9 g of the corresponding cross-linked random hydrogelcopolymer was obtained.

[0072] As the present disclosure shows, the molecular weights ofhydrogels having both thermo- and pH-responsive properties at the sametime can be controlled with the present invention. Thus, the presentinvention allows change of the physical properties of the hydrogels andthe polymerization yield according to the process of the presentinvention is higher than what is conventionally available. The catalystsremained after polymerization was conveniently removed because a polaror non-polar solvent was selectively used.

[0073] While the present invention has been described in detail and withreference to specific embodiments, it will become apparent to oneskilled in the art that various changes and modifications can be madewithout departing from the spirit and scope thereof.

What is claimed is:
 1. Random or block copolymer hydrogels represented by the following formulas (9) to (14):

R₁ is selected from the group consisting of phenyl, isoxazole, acetyl, methizole, dimethoxine, diazine, methoxypyridazine, methazine, isomidine and pyridine; R₂ represents hydrogen or methyl; m is 5 to 500; n is 3 to 500; and the ratio of y/x ranges from 2/98 to 8/92.
 2. A process for preparing copolymer hydrogels with controlled molecular weights and both thermo- and pH-responsive properties, which comprises the steps of: (a) providing sulfonamide type styrenic or (meth)acrylamide-based monomers exhibiting different pK_(a) values; (b) providing poly(N-isopropylacrylamide) or crosslinked poly(N-isopropylacrylamide-co-methylene bisacrylamide) having a thermo-responsive property; and (c) providing the sulfonamide type of homopolymers exhibiting different pH-sensitive properties and random or block copolymers of the sulfonamide type styrenic or (meth)acrylamide monomers prepared in step (a) with poly(N-isopropylacrylamide) or poly(N-isopropylacrylamide-co-methylene bisacrylamide) hydrogels prepared in step (b) in a polar or non-polar solvent; wherein said steps (b) and (c) are carried out by transition metal-mediated radical polymerization, using alkyl halides as the initiators, and catalysts with phosphine ligands represented by the following formula (4) or (5); or

R₁ to R₅ are selected from the group consisting of methyl, phenyl, iso-propyl, tert-butyl and ethyl; Mt is nickel or iron; X is chlorine or bromine; and n is 1 to 3; catalysts with the amine-based ligands being represented by the following formulas (6) to (8):

wherein R represents hydrogen, 5-nonyl or n-heptyl group.

wherein R represents n-propyl or n-butyl.


3. The process according to claim 2 wherein the sulfonamide type of styrenic monomers prepared in step (a) are the compounds represented by the following formula (1) or (2).

R₁ is selected from the group consisting of phenyl, isoxazole, acetyl, methizole, dimethoxine, diazine, methoxypyridazine, methazine, isomidine and pyridine.
 4. The process according to claim 2 wherein the sulfoneamide acryl-based monomers prepared in step (a) are the compounds represented by the following formula (3).

wherein R₁ is selected from the group consisting of phenyl, isoxazole, acetyl, methizole, dimethoxine, diazine, methoxypyridazine, methazine, isomidine and pyridine, and R₂ is hydrogen or a methyl group.
 5. The process according to claim 2, wherein the amine-based ligands are 2,2′:6′,6″-terpyridine or 1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene for the iron-based catalyst.
 6. The process according to claim 2, wherein the polar solvent is selected from the group consisting of dimethylformamide, dimethylsulfoxide, tetrahydrofuran, distilled water and solvents containing halogens and mixtures thereof; and the non-polar solvent is selected from the group consisting of hexane, toluene, benzene and cyclohexane. 